IRAS/Nischarin is associated with attenuated deficit of cognition during morphine abstinence in mice

Opioid withdrawal leads to impairments in cognitive functions that are now recognized as a major negative consequence and a key target for intervention in drug addiction. Imidazoline receptor antisera-selected (IRAS) protein is a candidate for the I1 imidazoline receptor. Studies have revealed that IRAS plays an important part in the development of morphine tolerance and dependence. Whether IRAS affects cognitive deficits caused by morphine during abstinence is not known. We investigated the effects of IRAS knockout on natural reward seeking, spatial memory, and reversal learning in male mice during the morphine withdrawal. We demonstrated that morphine abstinence led to the impairments of these cognitive functions. IRAS knockout mitigated the dysfunction of morphine abstinence on natural reward seeking, reduced the decline in spatial memory acquisition and retrieval caused by morphine withdrawal, and alleviated impairments in reversal learning abilities. Notably, mice with IRAS knockout demonstrated a significant increase in hippocampal neuron spine density and a marked enhancement of long-term potentiation in the CA1 region compared with their wild-type littermates during abstinence. IRAS knockout led to the activation of cyclic adenosine monophosphate-dependent protein kinase A and increased phosphorylation of the AMPA receptor GluR1 at Ser845, as well as the NMDA receptor subunits NR2A and NR2B, in the hippocampus. Together, our findings underscore the critical role of IRAS in modulating synaptic plasticity and cognitive deficits induced by morphine abstinence. IRAS could be a regulatory target for mitigating the cognitive impairments associated with opioid dependence.